Four major antiepileptic drugs (AEDs) are used for the treatment of epilepsy (epileptic seizures and convulsions): phenytoin, carbamazepine, phenobarbital and valproic acid (VPA). However, about 25% of the patients do not respond to the current medications. Furthermore, AEDs are administered repetitively as chronic treatment and the adverse effects associated with antiepileptic therapy are of a major concern. All the established AEDs are associated with some rare but severe side effects such as teratogenicity. In addition, all the AEDs have other adverse effects that limit their use. Valproic acid itself has considerable adverse effects including fatal hepatotoxicity.
One approach to obtain improved antiepileptic agents has been to prepare the primary amide derivatives of valproic acid and its analogs. Valnoctamide (VCD) and propyl-isoproylacetamide (PID) are amide derivatives of valproic acid that have improved anticonvulsant activity when compared to VPA. These amide analogues of valproic acid have been shown to be non-teratogenic, O. Spiegelstein, M. Bialer, M. Radatz, H. Nau and B. Yagen Chirality, 11:645–650 (1999).
Amide derivatives of Tetramethylcyclopropane carboxylic acid have also been previously evaluated for their anticonvulsant activity (M. Bialer, S. Hadad, B. Kadry, A. Abdul-Hai, A. Haj-Yehia, J. Sterling, Y Herzig and B. Yagen Pharm Res. 13:284–289 (1996)). These derivatives had good anticonvulsant activity (J. Sterling, et al. U.S. Pat. No. 5,880,157, issued March. 1999) and superior brain penetration than VPA. The N-Methyl-tetramethylcyclopropane carboxamide has a wide spectrum of anticonvulsant activity and is approximately 10 times more potent than VPA in animal models of epilepsy. In addition, N-Methyl-tetramethylcyclopropane carboxamide and Tetramethylcyclopropane carboxamide were not teratogenic in mouse model of antiepileptic drug induced teratogenicity.
Based on the success of VPA and VCD in treatment of nonepileptic disorders it is expected that an amide derivative of VPA will be effective in migraine, neuropathic pain and mania (bipolar disorders).